addition of (+)-(Z)-crotyldiisopinocampheylborane gave the
syn-homoallylic alcohol 5 as a single diastereomer (78%,
91% ee).11 The S configuration at the hydroxyl-bearing
methine group in 5 was confirmed by the modified Mosher
method.12 The homoallylic alcohol was again oxidized with
O3, followed by a Wittig reaction to generate the enoate in
two steps. Hydrogenation and transesterification of the enoate
yielded the lactone 6 in 71% after four steps.13 The treatment
of lactone 6 with KHMDS, DMPU, and Tf2NPh at -78 °C
gave ketene acetal triflate, which upon Stille coupling with
CH2dCHSnn-Bu3 generated the dienol ether 7. After hy-
droboration of 7, the product was treated with H2O2 to furnish
pyran 8 in 50% yield.14 The relative configurations of 8 were
confirmed by NOE correlations between H-8 and H-12, and
Me-18 on C-9 and H-11, and by the large proton coupling
constant of 9.2 Hz between H-11 and H-12.15 Steric
hindrance arising from the presence of the axial methyl group
of 7 generated the desired stereoselectivity of hydroboration
with thexylborane. Protection of the hydroxyl groups in 8
with TBSCl and subsequent selective deprotection of the TBS
group on the primary alcohol gave a primary alcohol, which
was oxidized to a carboxylic acid in 9 by treatment with
TEMPO, NaOCl, and TBAC in 80% yield. Introduction of
the terminal amino group was accomplished by means of
Curtius rearrangement. The carboxylic acid 9 was treated
with (PhO)2P(O)N3 (DPPA) and Et3N in toluene at 80 °C
for 4 h. The solvent was then replaced with THF, and treated
with 4 N LiOH to generate the amine 10 in 85% yield.16
The amino group was acetylated with acetic anhydride to
afford amide 11. At this point, NMR data were compared
between 11 and the natural product 1 to reconfirm the
stereochemical structure of 1 at the oxacyclic part. Although
the 13C chemical shifts around the amide region agreed well
by comparison of the HSQC data, any slight differences in
1H chemical shifts are attributable to the protective groups
on the hydroxyl functions or the truncated side chain in 11.
Selective deprotection of the TBDPS group with TBAF and
Scheme 1. Synthetic Strategy
thetic starter unit of 1 and hence may provide important
biogenetic clues to the origin and biosynthetic assembly of
polyethers in general.8 The chemical synthesis of 1 is
important to confirm the stereochemical details and at the
same time supply additional material for biological testing.
In this paper we report the total synthesis of 1 via
Suzuki-Miyaura cross-coupling as a key reaction, which
confirmed the stereochemical structure of the natural product.
The synthetic strategy employed was to build up both an
amino cyclic ether fragment 2 and an iododienol unit 3 from
a common starting material, cis-but-2-ene-1,4-diol 4, and then
couple these fragments by means of Suzuki-Miyaura
coupling (Scheme 1).9 In order to confirm the stereochemical
features of the amino cyclic ether moiety in 1 as early as
1
possible in the synthetic scheme, the H and 13C NMR
chemical shifts of 11 were compared with those of 1 and
found to be consistent with predicted 13C values. Therefore,
the acetylated amino group that was subject to a side reaction
was introduced before the Suzuki-Miyaura coupling reac-
tion. In our previous reports of polycyclic ether synthesis,
Suzuki-Miyaura coupling has been used for stereocontrolled
ether ring construction,10 but the method was applied to
extend the side chain from a terminal vinyl in this study.
Optically active homoallylic alcohol 5 was stereoselec-
tively prepared following reported procedures (Scheme 2).11
Diol 4 was protected with TBDPSCl and then oxidatively
cleaved with O3 to give the aldehyde. Generation of desired
configuration for the hydroxyl and methyl groups in 5 was
accomplished by Brown crotylation of this aldehyde. Thus
1
AcOH gave the desired primary alcohol. H and 13C NMR
spectra of the alcohol were shown as 17 in Supporting
Information. Oxidation of the alcohol in CH2Cl2-DMSO
with SO3·pyridine and Et3N gave a crude aldehyde product,
which without further purification was reacted with
Ph3PdCH2 in a Wittig reaction to furnish the ether ring
fragment 2.
Unsaturated aldehyde 12 prepared from 4 in three steps17
was treated with CBr4, PPh3, and Et3N to give dibromoolefin
13. Dehydrobromination with TBAF to give bromoacetylene
14 and subsequent debromination with n-BuLi at -78 °C
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(15) The carbon numbering corresponds to that of brevisamide (Scheme
1).
(16) Boger, D. L.; Cassidy, K. C.; Nakahara, S. J. Am. Chem. Soc. 1993,
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